This invention relates to cancer therapy and organic chemistry.
The psychoactive agent in Cannabis plant material is tetrahydrocannabinol (THC). Since THC is known to elicit various physiological effects (e.g., as an anti-inflammatory agent or analgesic) other than psychoactivity, various derivatives of THC that retain a favorable biochemical or pharmacological activity of THC without any potential for abuse or psychoactivity are beneficial and have been synthesized as potential drugs.
One of the activities associated with THC and some of its derivatives is inhibition of cell proliferation. However, this activity, as with psychoactivity, is dependent on binding to the cannabinoid receptor CB1 (Galve-Roperh et al., Nat. Med. 6:313-319, 2000; De Petrocellis et al., Proc. Natl. Acad. Sci. USA 95:8375-8380, 1998; and Bisogno et al., Eur. J. Biochem. 254:634-642, 1998). Thus, non-psychoactive derivatives of THC, which do not bind to the CB1 receptor (Burstein, Pharmacol. Ther. 82:87-96, 1999), are not expected to inhibit cell proliferation.
The invention is based on the discovery that non-psychoactive THC derivatives, such as THC acids, can decrease cell proliferation. Moreover, this effect is not dependent on an increase in the rate of apoptosis, which has been identified as a CB1 receptor-mediated activity of THC (Sanchez et al., FEBS Lett. 436:6-10, 1998).
Accordingly, the invention features a method of decreasing cell proliferation in a mammal (e.g., a human) by identifying a mammal in which a decrease in cell proliferation is desirable, and administering to the mammal an amount of a compound of Formula I effective to decrease cell proliferation in the mammal, 
where R1 is a hydrogen atom, xe2x80x94COCH3, or xe2x80x94COCH2CH3; and R2 is a branched C5-C12 alkyl. R1 can be hydrogen, and R2 can be a C9 alkyl, which can be a branched alkyl such as 1,1-dimethylheptyl.
The compound can be administered orally (e.g., as a dietary supplement), systemically, intravenously, or via an implant, which can provide slow release of the compound. In addition, the compound can be administered for treatment of a pre-existing disease or condition that is characterized by cell proliferation, or for prophylaxis against such a disease or condition. The compound can be administered to the mammal at a dose of about 0.1 to 20 mg/kg body weight (e.g., about 0.2 to 2 mg/kg body weight) to effectively decrease cell proliferation. The method is particularly useful in treating a mammal that is suffering from cancer.
In addition, a cell in vitro can be contacted with the compound to decrease or abolish the cell""s ability to proliferate.
As used herein, xe2x80x9ccell proliferationxe2x80x9d means an increase in cell number. By xe2x80x9cdecreasing cell proliferationxe2x80x9d is meant a decrease in cell proliferation that is not solely due to an increase in apoptosis.
As used herein, xe2x80x9calkylxe2x80x9d means a straight or branched hydrocarbon chain containing carbon atoms or cyclic hydrocarbon moieties. These alkyl groups may also contain one or more double bonds or triple bonds. By xe2x80x9csubstituted alkylxe2x80x9d is meant an alkyl in which an atom of the alkyl is substituted with an atom, e.g., a sulfur, oxygen, or halogen atom.
The methods of the invention provide a new use for non-psychoactive cannabinoids as drugs for the treatment or prophylaxis of a condition or disease characterized by cell proliferations (e.g., cancer). Because of the low toxicity, non-psychoactive nature, and low abuse potential of such cannabinoids, the compounds can be used as a dietary supplement (e.g., like a daily vitamin pill) to prevent cancer. In addition, the compounds can be applied topically, e.g., to a skin lesion characterized by undesirable cell proliferation, such as in psoriasis.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although suitable methods and materials for the practice or testing of the present invention are described below, other methods and materials similar or equivalent to those described herein, which are well known in the art, can also be used. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.